3-152432745-C-T

Position:

• chr3-152432745-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021038.5(MBNL1):​c.374C>T​(p.Ala125Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MBNL1 NM_021038.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.19

Genes affected

MBNL1 (HGNC:6923): (muscleblind like splicing regulator 1) This gene encodes a member of the muscleblind protein family which was initially described in Drosophila melanogaster. The encoded protein is a C3H-type zinc finger protein that modulates alternative splicing of pre-mRNAs. Muscleblind proteins bind specifically to expanded dsCUG RNA but not to normal size CUG repeats and may thereby play a role in the pathophysiology of myotonic dystrophy. Mice lacking this gene exhibited muscle abnormalities and cataracts. Several alternatively spliced transcript variants have been described but the full-length natures of only some have been determined. The different isoforms are thought to have different binding specificities and/or splicing activities. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBNL1	NM_021038.5	c.374C>T	p.Ala125Val	missense_variant	4/10	ENST00000324210.10	NP_066368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBNL1	ENST00000324210.10	c.374C>T	p.Ala125Val	missense_variant	4/10	1	NM_021038.5	ENSP00000319429	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.374C>T (p.A125V) alteration is located in exon 3 (coding exon 3) of the MBNL1 gene. This alteration results from a C to T substitution at nucleotide position 374, causing the alanine (A) at amino acid position 125 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T;T;.;.;T;.;T;.;.;.;T;.;.;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;D;.;.;.;D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.3	M;.;M;.;.;M;.;.;M;M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.2	N;.;N;D;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.037	D;.;D;D;D;D;T;D;T;D;D;T;D;D
Sift4G	Benign	0.17	T;T;T;D;T;T;T;T;T;T;T;T;T;T
Polyphen		0.71	P;.;P;.;B;.;.;D;.;.;P;.;.;.
Vest4		0.78
MutPred		0.15		Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);.;.;Loss of relative solvent accessibility (P = 0.0071);.;Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);.;
MVP		0.54
MPC		1.9
ClinPred		0.96	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-152150534;